Nitric oxide is a major intercellular signal in humans and other animals that affects many different organ systems. Important actions caused by nitric oxide include vasodilation, smooth muscle relaxation in the gastrointestinal tract, lungs, and uterus, and many neurological functions including pain perception. Many of the actions of nitric oxide are actually caused by compounds, known as S-nitrosothiols or thionitrites, that are derived from nitric oxide and specific thiols. Some of the actions of S-nitrosothiols occur at stereospecific recognition sites that are selective for specific nitrosothiols.
One pathological condition in humans that is caused by the overproduction of nitric oxide is septic shock. The profound hypotension, tissue ischemia, and organ failure of septic shock are rare sequellae to infection yet septic shock is the leading cause of death in intensive care units. The hypotension is largely the result of massive vasodilation in the patient with hypoperfusion and organ failure, including cardiac failure, exacerbating the problem. Vasodilation is initiated by bacterial endotoxins which trigger a series of host defense mechanisms including greatly increased expression of the inducible isozyme of nitric oxide synthase (iNOS). Treatment of septic shock, in addition to treatment of the underlying infection, consists of administration of intravenous fluids and vasopressors, although these therapies are less effective in septic patients than non-septic patients. Decreasing the production of nitric oxide (NO) with inhibitors of nitric oxide synthase such as Nω-nitro-L-arginine methyl ester (L-NAME) or L-NGmethylarginine (L-NMMA) is a logical therapy, but results in both animals and humans have not been encouraging. Heart failure and continued high mortality commonly follow such treatment.
Current treatment options for hypotension or shock from such conditions such as septic shock, toxic shock syndrome, spinal cord injury, effects of anesthetics, and anaphylaxis, etc. are limited to vasoconstricting agents that have many deleterious side effects that limit their effective therapeutic usage.
It therefore can be seen that there is a continuing need for the development of effective pharmacological treatments to counteract hypotension and shock. In particular, there is no effective treatment presently available that specifically counteracts the hypotension caused by the relative overproduction of nitric oxide and nitrosothiols as present in such conditions as septic shock. This invention has as its primary objective the fulfillment of this need.
Other objectives of the present invention include both processes, compositions and treatments useful to treat the undesired effects of nitric oxide and nitrosothiol production. Conditions other than hypotension that might benefit from inhibition of the actions of nitric oxide and nitrosothiols includes but are not limited to, chronic and acute pain, hypoxemia secondary in part to the loss of hypoxic pulmonary vasoconstriction, uterine atony, and decreased tone and peristalsis of gastrointestinal smooth muscle.